RESUMO
The marketed drug Doxorubicin (DOX) and the promising anti-cancer agent 9-(N-piperazinyl)-5-methyl-12(H)-quino[3,4-b][1,4]benzothiazinium chloride (9-PBThACl) were used to prepare and compare a range of liposomal delivery systems based on dipalmitoylphosphatidylcholine (DPPC). Liposome-assisted drug release was examined using the spectrophotometric method. In order to provide in vitro release characteristics of liposomal conjugates (LDPPC/drug vs. LDPPC/drug/drug) as well as to evaluate the impact of temperature and pH buffering on the conformation/polarity of the phospholipid bilayer, the encapsulation efficiency of the liposomes entrapping 9-PBThACl and DOX was calculated. In fact, some competition between the investigated molecules was noticed during the entrapment process because relatively high values of the encapsulation efficiency were observed only for the liposomal complexes containing one trapped drug molecule. An averaged absorbance value enabled us to indicate the pH value of the environment (pH ≈ 6.8), at which the physicochemical property profiles of the liposomal complexes were noticeably changed. Moreover, the operational factors limiting the drug release kinetics from the produced liposomes were mathematically modeled. First-order and Bhaskas models ensured satisfactory compliance with the experimental data for the liposomal complexes buffered at pH values of 5.50, 6.00, and 7.40, respectively.
Assuntos
Doxorrubicina , Lipossomos , Lipossomos/química , Temperatura , Liberação Controlada de Fármacos , Doxorrubicina/química , Concentração de Íons de Hidrogênio , Sistemas de Liberação de MedicamentosRESUMO
A series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102 highlighted that 23 compounds possessed IC50 < 30 µM. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC50 = 1.6 µM was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 µM. A good correlation between the experimental logk and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated N-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an 'averaged' selection-driven interaction pattern was produced based in namely 'pseudo-consensus' 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds.
Assuntos
Antimaláricos , Antimaláricos/farmacologia , Arginase/farmacologia , Simulação de Acoplamento Molecular , Cloroquina/farmacologia , Plasmodium falciparum , Relação Estrutura-AtividadeRESUMO
In this paper, we describe a new method for synthesizing hybrid combinations of 1,2,3-triazoles with a tetracyclic quinobenzothiazinium system. The developed approach allowed for the production of a series of new azaphenothiazine derivatives with the 1,2,3-triazole system in different positions of the benzene ring. In practice, the methodology consists of the reaction of triazole aniline derivatives with thioquinanthrenediinium bis-chloride. The structure of the products was determined by 1H-NMR, 13C-NMR spectroscopy, and HR-MS spectrometry, respectively. Moreover, the spatial structure of the molecule and the arrangement of molecules in the crystal (unit cell) were determined by X-ray crystallography. The anticancer activity profiles of the synthesized compounds were tested in vitro against human cancer cells of the A549, SNB-19, and T47D lines and the normal NHDF cell line. Additional tests of antibacterial activity against methicillin-sensitive and methicillin-resistant staphylococci, vancomycin-sensitive and vancomycin-resistant enterococci, and two mycobacterial strains were also performed. In fact, the dependence of anticancer and antibacterial activity on the substituent type and its position in the quinobenzothiazinium system was observed. Furthermore, the distance-guided property evaluation was performed using principal component analysis (PCA) and hierarchical clustering analysis (HCA) on the pool of the calculated descriptors. Finally, the theoretically approximated partition coefficients (clogP) were (inter-)correlated with each other and cross-compared with the empirically specified logPTLC parameters.
Assuntos
Antibacterianos , Vancomicina , Humanos , Antibacterianos/farmacologia , Linhagem Celular , Cloretos , Análise por ConglomeradosRESUMO
A new method for modifying the structure of tetracyclic quinobenzothiazinium derivatives has been developed, allowing introduction of various substituents at different positions of the benzene ring. The method consists of reacting appropriate aniline derivatives with 5,12-(dimethyl)thioquinantrenediinium bis-chloride. A series of new quinobenzothiazine derivatives was obtained with propyl, allyl, propargyl and benzyl substituents in 9, 10 and 11 positions, respectively. The structure of the obtained compounds was analyzed by 1H and 13C NMR (HSQC, HMBC) and X-ray analysis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212, and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). In addition, all the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. 9-Benzyloxy-5-methyl-12H-quino [3,4-b][1,4]benzothiazinium chloride (6j), 9-propoxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (6a) and 9-allyloxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (6d) demonstrated high activity against the entire tested microbial spectrum. The activities of the compounds were comparable with oxacillin, tetracycline and ciprofloxacinagainst staphylococcal strains and with rifampicin against both mycobacterial strains. Compound 6j had a significant effect on the inhibition of bacterial respiration as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity, but also bactericidal activity. Preliminary in vitro cytotoxicity screening of the compounds performed using normal human dermal fibroblasts (NHDF) proved that the tested compounds showed an insignificant cytotoxic effect on human cells (IC50 > 37 µM), making these compounds interesting for further investigation. Moreover, the intermolecular similarity of novel compounds was analyzed in the multidimensional space (mDS) of the structure/property-related in silico descriptors by means of principal component analysis (PCA) and hierarchical clustering analysis (HCA), respectively. The distance-oriented structure/property distribution was related with the experimental lipophilic data.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Mycobacterium , Humanos , Testes de Sensibilidade Microbiana , Cloretos/farmacologia , Antibacterianos/químicaRESUMO
The knowledge of interactions between different molecules is undoubtedly the driving force of all contemporary biomedical and biological sciences. Chemical biology/biological chemistry has become an important multidisciplinary bridge connecting the perspectives of chemistry and biology to the study of small molecules/peptidomimetics and their interactions in biological systems. Advances in structural biology research, in particular linking atomic structure to molecular properties and cellular context, are essential for the sophisticated design of new medicines that exhibit a high degree of druggability and very importantly, druglikeness. The authors of this contribution are outstanding scientists in the field who provided a brief overview of their work, which is arranged from in silico investigation through the characterization of interactions of compounds with biomolecules to bioactive materials.
Assuntos
Biologia MolecularRESUMO
A key question confronting computational chemists concerns the preferable ligand geometry that fits complementarily into the receptor pocket. Typically, the postulated 'bioactive' 3D ligand conformation is constructed as a 'sophisticated guess' (unnecessarily geometry-optimized) mirroring the pharmacophore hypothesis-sometimes based on an erroneous prerequisite. Hence, 4D-QSAR scheme and its 'dialects' have been practically implemented as higher level of model abstraction that allows the examination of the multiple molecular conformation, orientation and protonation representation, respectively. Nearly a quarter of a century has passed since the eminent work of Hopfinger appeared on the stage; therefore the natural question occurs whether 4D-QSAR approach is still appealing to the scientific community? With no intention to be comprehensive, a review of the current state of art in the field of receptor-independent (RI) and receptor-dependent (RD) 4D-QSAR methodology is provided with a brief examination of the 'mainstream' algorithms. In fact, a myriad of 4D-QSAR methods have been implemented and applied practically for a diverse range of molecules. It seems that, 4D-QSAR approach has been experiencing a promising renaissance of interests that might be fuelled by the rising power of the graphics processing unit (GPU) clusters applied to full-atom MD-based simulations of the protein-ligand complexes.
Assuntos
Algoritmos , Relação Quantitativa Estrutura-Atividade , Gráficos por Computador , Modelos Moleculares , Conformação MolecularRESUMO
A series of new tertiary phenothiazine derivatives containing a quinoline and a pyridine fragment was synthesized by the reaction of 1-methyl-3-benzoylthio-4-butylthioquinolinium chloride with 3-aminopyridine derivatives bearing various substituents on the pyridine ring. The direction and mechanism of the cyclization reaction of intermediates with the structure of 1-methyl-4-(3-pyridyl)aminoquinolinium-3-thiolate was related to the substituents in the 2- and 4-pyridine position. The structures of the compounds were analyzed using 1H, 13C NMR (COSY, HSQC, HMBC) and X-ray analysis, respectively. Moreover, the antiproliferative activity against tumor cells (A549, T47D, SNB-19) and a normal cell line (NHDF) was tested. The antibacterial screening of all the compounds was conducted against the reference and quality control strain Staphylococcus aureus ATCC 29213, three clinical isolates of methicillin-resistant S. aureus (MRSA). In silico computation of the intermolecular similarity was performed using principal component analysis (PCA) and hierarchical clustering analysis (HCA) on the pool of structure/property-related descriptors calculated for the novel tetracyclic diazaphenothiazine derivatives. The distance-oriented property evaluation was correlated with the experimental anticancer activities and empirical lipophilicity as well. The quantitative shape-based comparison was conducted using the CoMSA method in order to indicate the potentially valid steric, electronic and lipophilic properties. Finally, the numerical sampling of similarity-related activity landscape (SALI) provided a subtle picture of the SAR trends.
Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Compostos Heterocíclicos/química , Neoplasias/tratamento farmacológico , Fenotiazinas/química , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Antineoplásicos/química , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl (3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 µM in the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure-activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.
Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/síntese química , Simulação de Acoplamento Molecular , Acetilcolinesterase/metabolismo , Ácido Aminossalicílico/química , Butirilcolinesterase/metabolismo , Carbamatos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Análise por Conglomerados , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Moleculares , Simulação de Dinâmica Molecular , Análise de Componente Principal , Solventes , Relação Estrutura-Atividade , Células THP-1RESUMO
We synthesized a series of novel 3-carboranyl-1,8-naphthalimide derivatives, mitonafide and pinafide analogs, using click chemistry, reductive amination and amidation reactions and investigated their in vitro effects on cytotoxicity, cell death, cell cycle, and the production of reactive oxygen species in a HepG2 cancer cell line. The analyses showed that modified naphthalic anhydrides and naphthalimides bearing ortho- or meta-carboranes exhibited diversified activity. Naphthalimides were more cytotoxic than naphthalic anhydrides, with the highest IC50 value determined for compound 9 (3.10 µM). These compounds were capable of inducing cell cycle arrest at G0/G1 or G2M phase and promoting apoptosis, autophagy or ferroptosis. The most promising conjugate 35 caused strong apoptosis and induced ROS production, which was proven by the increased level of 2'-deoxy-8-oxoguanosine in DNA. The tested conjugates were found to be weak topoisomerase II inhibitors and classical DNA intercalators. Compounds 33, 34, and 36 fluorescently stained lysosomes in HepG2 cells. Additionally, we performed a similarity-based assessment of the property profile of the conjugates using the principal component analysis. The creation of an inhibitory profile and descriptor-based plane allowed forming a structure-activity landscape. Finally, a ligand-based comparative molecular field analysis was carried out to specify the (un)favorable structural modifications (pharmacophoric pattern) that are potentially important for the quantitative structure-activity relationship modeling of the carborane-naphthalimide conjugates.
Assuntos
Antineoplásicos , Substâncias Intercalantes , Naftalimidas , Neoplasias , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Células Hep G2 , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Naftalimidas/síntese química , Naftalimidas/química , Naftalimidas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
A series of twenty-two novel N-(disubstituted-phenyl)-3-hydroxynaphthalene- 2-carboxamide derivatives was synthesized and characterized as potential antimicrobial agents. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[2-chloro-5-(trifluoromethyl)phenyl]-3-hydroxy- naphthalene-2-carboxamide showed submicromolar (MICs 0.16-0.68 µM) activity against methicillin-resistant Staphylococcus aureus isolates. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[4-bromo-3-(trifluoromethyl)phenyl]-3-hydroxynaphthalene-2-carboxamide revealed activity against M. tuberculosis (both MICs 10 µM) comparable with that of rifampicin. Synergistic activity was observed for the combinations of ciprofloxacin with N-[4-bromo-3-(trifluoromethyl)phenyl]- and N-(4-bromo-3-fluorophenyl)-3-hydroxynaphthalene-2-carboxamides against MRSA SA 630 isolate. The similarity-related property space assessment for the congeneric series of structurally related carboxamide derivatives was performed using the principal component analysis. Interestingly, different distribution of mono-halogenated carboxamide derivatives with the -CF3 substituent is accompanied by the increased activity profile. A symmetric matrix of Tanimoto coefficients indicated the structural dissimilarities of dichloro- and dimetoxy-substituted isomers from the remaining ones. Moreover, the quantitative sampling of similarity-related activity landscape provided a subtle picture of favorable and disallowed structural modifications that are valid for determining activity cliffs. Finally, the advanced method of neural network quantitative SAR was engaged to illustrate the key 3D steric/electronic/lipophilic features of the ligand-site composition by the systematic probing of the functional group.
Assuntos
Anti-Infecciosos/síntese química , Staphylococcus aureus Resistente à Meticilina , Mycobacterium tuberculosis , Naftalenos/química , Testes de Sensibilidade MicrobianaRESUMO
A series of nineteen novel ring-substituted N-arylcinnamanilides was synthesized and characterized. All investigated compounds were tested against Staphylococcus aureus as the reference strain, two clinical isolates of methicillin-resistant S. aureus (MRSA), and Mycobacterium tuberculosis. (2E)-N-[3-Fluoro-4-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide showed even better activity (minimum inhibitory concentration (MIC) 25.9 and 12.9 µM) against MRSA isolates than the commonly used ampicillin (MIC 45.8 µM). The screening of the cell viability was performed using THP1-Blue™ NF-κB cells and, except for (2E)-N-(4-bromo-3-chlorophenyl)-3-phenylprop-2-enamide (IC50 6.5 µM), none of the discussed compounds showed any significant cytotoxic effect up to 20 µM. Moreover, all compounds were tested for their anti-inflammatory potential; several compounds attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. The lipophilicity values were specified experimentally as well. In addition, in silico approximation of the lipophilicity values was performed employing a set of free/commercial clogP estimators, corrected afterwards by the corresponding pKa calculated at physiological pH and subsequently cross-compared with the experimental parameters. The similarity-driven property space evaluation of structural analogs was carried out using the principal component analysis, Tanimoto metrics, and Kohonen mapping.
Assuntos
Cinamatos/síntese química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Ampicilina/farmacologia , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Inflamação , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Micro-Ondas , Modelos Moleculares , NF-kappa B/metabolismo , Análise de Componente Principal , Relação Estrutura-Atividade , Células THP-1RESUMO
Chemically functionalized graphene oxides could be used as novel drug carriers. Covalent alterations of graphene oxides lead to surface changes via formation of chemical bonding while non-covalent ones involve van der Waals forces, hydrogen bonding, and π-π stacking interactions. Covalent modifications appear to be superior as they can yield compounds with desired properties and carriers prepared by other methods are less stable. Synthesis of graphene oxide-iminodiacetic acid and graphene oxide-glycine involves nucleophilic substitution of graphene oxide nanoparticles with iminodiacetic acid or glycine. As the first step, iminodiacetic acid or glycine were transformed into iminodiacetic acid or glycine methyl ester hydrochlorides, respectively, for C-terminus protection. The obtained product, activated in situ, was then used to form amide bonds between graphene oxide and iminodiacetic acid or glycine.
Assuntos
Grafite , Portadores de Fármacos , Ligação de Hidrogênio , ÓxidosRESUMO
Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3',3'-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 µM and 0.03 µM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)-spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.
Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Compostos Organofosforados/síntese química , Succinatos/química , Triterpenos/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Linhagem Celular , HIV-1/metabolismo , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismoRESUMO
A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structureâ»activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the hostâ»target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.
Assuntos
Acetilcolinesterase/metabolismo , Benzeno/química , Benzeno/farmacologia , Butirilcolinesterase/metabolismo , Carbamatos/química , Carbamatos/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Animais , Benzeno/síntese química , Carbamatos/síntese química , Inibidores da Colinesterase/síntese química , Desenho de Fármacos , Electrophorus , Cavalos , Concentração Inibidora 50 , Ligantes , Simulação de Acoplamento Molecular , Análise de Componente Principal , Probabilidade , Relação Estrutura-AtividadeRESUMO
A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron®, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (2) and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (3) were characterized by fairly high selective indexes. Specifically, compound 2 was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules 3 and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (4) are in line with rivastigmine activity. Moreover, a structure-activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity-activity landscape index for BChE inhibitory response values. The 'indirect' ligand-based and 'direct' protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an 'average' 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystem II (PSII).
Assuntos
Carbamatos/química , Carbamatos/farmacologia , Inibidores da Colinesterase/química , Silício/química , Sítios de Ligação , Butirilcolinesterase , Sobrevivência Celular/efeitos dos fármacos , Cloroplastos , Inibidores da Colinesterase/farmacologia , Transporte de Elétrons/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Simulação de Acoplamento Molecular , Complexo de Proteína do Fotossistema II , Spinacia oleracea , Relação Estrutura-Atividade , Células THP-1/efeitos dos fármacosRESUMO
A series of twenty-six methoxylated and methylated N-aryl-1-hydroxynaphthalene- 2-carboxanilides was prepared and characterized as potential anti-invasive agents. The molecular structure of N-(2,5-dimethylphenyl)-1-hydroxynaphthalene-2-carboxamide as a model compound was determined by single-crystal X-ray diffraction. All the analysed compounds were tested against the reference strain Staphylococcus aureus and three clinical isolates of methicillin-resistant S. aureus as well as against Mycobacterium tuberculosis and M. kansasii. In addition, the inhibitory profile of photosynthetic electron transport in spinach (Spinacia oleracea L.) chloroplasts was specified. In vitro cytotoxicity of the most effective compounds was tested on the human monocytic leukaemia THP-1 cell line. The activities of N-(3,5-dimethylphenyl)-, N-(3-fluoro-5-methoxy-phenyl)- and N-(3,5-dimethoxyphenyl)-1-hydroxynaphthalene-2-carbox- amide were comparable with or even better than the commonly used standards ampicillin and isoniazid. All promising compounds did not show any cytotoxic effect at the concentration >30 µM. Moreover, an in silico evaluation of clogP features was performed for the entire set of the carboxamides using a range of software lipophilicity predictors, and cross-comparison with the experimentally determined lipophilicity (log k), in consensus lipophilicity estimation, was conducted as well. Principal component analysis was employed to illustrate noticeable variations with respect to the molecular lipophilicity (theoretical/experimental) and rule-of-five violations. Additionally, ligand-oriented studies for the assessment of the three-dimensional quantitative structure-activity relationship profile were carried out with the comparative molecular surface analysis to determine electron and/or steric factors that potentially contribute to the biological activities of the investigated compounds.
Assuntos
Anilidas/farmacologia , Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Mycobacterium kansasii/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Naftóis/farmacologia , Ampicilina/farmacologia , Anilidas/síntese química , Anilidas/química , Antibacterianos/síntese química , Antibacterianos/química , Cloroplastos/efeitos dos fármacos , Cloroplastos/fisiologia , Transporte de Elétrons/efeitos dos fármacos , Humanos , Isoniazida/farmacologia , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Metilação , Testes de Sensibilidade Microbiana , Mycobacterium kansasii/crescimento & desenvolvimento , Mycobacterium tuberculosis/crescimento & desenvolvimento , Naftóis/síntese química , Naftóis/química , Fotossíntese/efeitos dos fármacos , Análise de Componente Principal , Spinacia oleracea/química , Spinacia oleracea/efeitos dos fármacos , Spinacia oleracea/metabolismo , Relação Estrutura-Atividade , Células THP-1RESUMO
The evaluation of the lipophilic characteristics of biologically active agents is indispensable for the rational design of ADMET-tailored structureâ»activity models. N-Alkoxy-3-hydroxynaphthalene-2-carboxanilides, N-alkoxy-1-hydroxynaphthalene-2-carboxanilides, and N-alkoxy-2-hydroxynaphthalene-1-carboxanilides were recently reported as a series of compounds with antimycobacterial, antibacterial, and herbicidal activity. As it was found that the lipophilicity of these biologically active agents determines their activity, the hydro-lipophilic properties of all three series were investigated in this study. All 57 anilides were analyzed using the reversed-phase high-performance liquid chromatography method for the measurement of lipophilicity. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using an end-capped non-polar C18 stationary reversed-phase column. In the present study, a range of software lipophilicity predictors for the estimation of clogP values of a set of N-alkoxyphenylhydroxynaphthalenecarboxamides was employed and subsequently cross-compared with experimental parameters. Thus, the empirical values of lipophilicity (logk) and the distributive parameters (π) were compared with the corresponding in silico characteristics that were calculated using alternative methods for deducing the lipophilic features. To scrutinize (dis)similarities between the derivatives, a PCA procedure was applied to visualize the major differences in the performance of molecules with respect to their lipophilic profile, molecular weight, and violations of Lipinski's Rule of Five.
Assuntos
Anilidas/química , Naftalenos/química , Cromatografia de Fase Reversa , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The pharmacophore properties of a new series of potential purinoreceptor (P2X) inhibitors determined using a coupled neural network and the partial least squares method with iterative variable elimination (IVE-PLS) are presented in a ligand-based comparative study of the molecular surface by comparative molecular surface analysis (CoMSA). Moreover, we focused on the interpretation of noticeable variations in the potential selectiveness of interactions of individual inhibitor-receptors due to their physicochemical properties; therefore, the library of artificial dipeptide receptors (ADP) was designed and examined. The resulting library response to individual inhibitors was arranged in the array, preprocessed and transformed by the principal component analysis (PCA) and PLS procedures. A dominant absolute contribution to PC1 of the Glu attached to heptanoic gating acid and Phe bonded to the linker m-phenylenediamine/triazine scaffold was revealed by the PCA. The IVE-PLS procedure indicated the receptor systems with predominant Pro bonded to the linker and Glu, Gln, Cys and Val directly attached to the gating acid. The proposed comprehensive ligand-based and simplified structure-based methodology allows the in-depth study of the performance of peptide receptors against the tested set of compounds.
Assuntos
Dipeptídeos/química , Biblioteca de Peptídeos , Relação Quantitativa Estrutura-Atividade , Desenho de Fármacos , Modelos Moleculares , Redes Neurais de Computação , Análise de Componente Principal , Receptores ArtificiaisRESUMO
A rapid, simple to use and low-cost thin-layer chromatographic procedure in normal phase system with densitometric detection at 246 nm was carefully validated according to the International Conference on Harmonisation (ICH) guidelines for assay of clobetasol propionate in topical solution containing clobetasol propionate in quantity 0.50 mg/mL. The adopted thin-layer chromatographic (TLC)-densitometric procedure could effectively separate clobetasol propionate from its related compound, namely clobetasol. It is linear for clobetasol propionate in the range of 0.188 ÷ 5 µg/spot. The limit of detection (LOD) and limit of quantification (LOQ) value is 0.061 and 0.186 µg/spot, respectively. Accuracy of proposed procedure was evaluated by recovery test. The mean recovery of studied clobetasol propionate ranges from 98.7 to 101.0%. The coefficient of variation (CV, %) obtained during intra-day and inter-day studies, which was less than 2% (0.40 ÷ 1.17%), confirms the precision of described method. The assay value of clobetasol propionate is consistent with the pharmacopoeial requirements. In conclusion, it can be suitable as a simple and economic procedure for routine quality control laboratories of clobetasol propionate in topical solution.
Assuntos
Anti-Inflamatórios/análise , Cromatografia em Camada Fina/métodos , Clobetasol/análise , Densitometria/métodos , Bioensaio/métodos , Limite de Detecção , Reprodutibilidade dos TestesRESUMO
Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 µM) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and benzyl (2S)-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 µM, respectively) comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S)-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure-inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3'-/4'-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.